Download Epidemiology of bacterial meningitis

 Done by :
 Lina Wahbeh
 Dania Al Shafeey
 Maysoon Najdawi
 Jud Mohammad
 Lama Diab
 Hadeel Ma'ani
MENINGITIS
*Abstract
Infections of the central nervous system (CNS) can be divided into 2 broad categories: those primarily
involving the meninges and those primarily confined to the parenchyma (encephalitis). Meningitis is either
infectious (contagious) or noninfectious. Infectious meningitis is classified as viral, bacterial, fungal, or
parasitic, depending on the type of organism causing the infection, however, the aim of this review is to
discuss bacterial infection which is one of the most common causes of meningitis beside the viral infection. [1]
*Introduction
Meningitis is a clinical syndrome characterized by inflammation of the meninges. In bacterial meningitis the
organisms usually enter the meninges through the bloodstream from other parts of the body and in most cases
they get localized over the dorsum of the brain; however, under certain conditions, meningitis may be
concentrated at the base of the brain, as with fungal diseases and tuberculosis.
-What is meningitis?
Meningitis is a serious disease caused by the inflammation of the meninges, that envelope the brain and spinal
cord.
The most common cause of meningeal inflammation is bacterial
or viral infection.
Bacteria usually enter the bloodstream and travel to the brain
and spinal cord causing acute bacterial meningitis. But it can
also occur when bacteria directly invade the meninges. This
may be caused by an ear or sinus infection, a skull fracture, or,
rarely, after some surgeries.
Bacterial meningitis is an extremely serious illness that requires
immediate medical care. If not treated quickly, it can lead to death within hours or lead to permanent damage
to the brain.
-The most common bacteria causing meningitis are:
1. Streptococcus pneumoniae (pneumococcus): This bacterium is the most common cause of bacterial
meningitis in infants, young children and adults.
2. Neisseria meningitidis (meningococcus).
3. Haemophilus influenzae (haemophilus): Haemophilus influenzae type b (Hib) bacterium was once the
leading cause of bacterial meningitis in children. But new Hib vaccines have greatly reduced the number of
cases of this type of meningitis.
4. Listeria monocytogenes (listeria): Pregnant women, newborns, older adults and people with weakened
immune systems are most susceptible.
-Risk factors:
1. Extremes of age (< 5 or >60 years).
2. Diabetes mellitus, chronic kidney failure, adrenal insufficiency, hypoparathyroidism, or cystic fibrosis.
3. Compromised immune system like AIDS, alcoholism, use of immunosuppressant drugs.
4. Recent exposure to others with meningitis, with or without prophylaxis.
5. Malignancy.
6. Pregnancy.
[2,3]
*Pathophysiology
Most cases of meningitis are caused by infectious agents that colonized in the host; the main sites of
colonization are the skin, the nasopharynx, the respiratory tract, the gastrointestinal (GI) tract, and the
genitourinary tract.
-These infectious agents like bacteria can arrive the CNS via 3 pathways:



Invasion of the bloodstream and subsequent hematogenous seeding of the CNS ,this is the most common
pathway, and organism like meningococcal and pneumococcal meningitis can cause meningitis via this route.
A retrograde neuronal (e.g., olfactory and peripheral nerves) pathway
Direct contiguous spread (e.g., sinusitis, otitis media), and the migration pathway to meninges is possibly by:
The bloodstream.
Preformed tissue planes (e.g., posterior fossa).
Temporal bone fractures.
The oval or round window membranes of the labyrinths.
Meningitis in newborn can be transmitted either vertically e.g (pathogens that have colonized the maternal
intestinal or genital tract), or horizontally, via nursery personnel or caregivers at home.
The brain in normal conditions is protected from the body's immune system by the presence of the barrier that
the meninges create between the bloodstream and the brain. Normally, this barrier is an advantage because it
prevents the immune system from attacking the brain. However, in meningitis, the blood-brain barrier can
become disrupted; once bacteria or other organisms have found their way to the brain, they are somewhat
isolated from the immune system and can spread. So as usual the body tries to fight the foreign pathogen but
in this case the condition becomes worse because the blood vessels will be leaky and the WBC, fluid and
others will enter the meninges and brain which will cause brain swelling, decreasing blood flow to brain and
worsening the symptom of the infection.
Depending on severity, the inflammatory process may remain confined to the subarachnoid space and in less
severe cases the pial barrier is not going to be penetrated and parenchyma will stay intact. However, in severe
cases the pial barriers become penetrated, bleached and invaded by the inflammatory process. Thus, bacterial
meningitis may lead to widespread destruction, especially if untreated.
-Exudates may extend to basal cistern resulting in:



Damage to cranial nerves (e.g., cranial nerve VIII, with resultant hearing loss).
Obliteration of CSF pathways (causing obstructive hydrocephalus).
Induction of vasculitis and thrombophlebitis (causing local brain ischemia).
-Factors that immortalize the infectious process in meningitis are:

Replicating bacteria.



Increasing numbers of inflammatory cells.
Cytokine-induced disruptions in membrane transport.
Increased vascular and membrane permeability.
All of these processes make changes in CSF cell count, pH, lactate, protein, and glucose in patients. [4,5]
*Etiology of bacterial meningitis
There are many microorganisms that can cause meningitis including bacteria, viruses, fungi, parasites; also
drugs may be a cause (e.g., NSAIDs, metronidazole, and IV immunoglobulin).
-Bacteria that cause meningitis include:
1. Pachymeningitis: usually result from infection by staphylococcal or streptococcal; often reach the meninges
by skull defect, or an infection from paranasal sinuses or cranial osteomyelitis.
2. Haemophilus influenzae meningitis: H. influenza found in normal flora of upper respiratory tract so it can
move from organism to another via airborne droplet or direct contact of secretion. Previously, H influenza was
the most common cause of meningitis - mainly the encapsulated type b strain (Hib) - until Hib vaccine was
introduced which decrease the incidence of H. influenza meningitis by 35% of cases.
3. Pneumococcal meningitis: it is the most common bacterial agent in meningitis associated with basilar skull
fracture and CSF leak. It could be also associated with pneumonia, sinusitis, or endocarditic.
4. S. pneumoniae is a common colonizer of the human nasopharynx; it causes meningitis by escaping local
host defenses and phagocytic mechanisms by 2 pathways:


Choroid plexus seeding from bacteremia
Direct extension from sinusitis or otitis media.
5. Streptococcus agalactiae meningitis: it is colonized usually in lower GI tract and female genital tract and that
explains why it is the main cause of 70% of neonatal meningitis.
6. Meningococcal meningitis: N meningitidis in healthy individuals it is carried in nasopharynx, it invades by
penetrating the airway epithelial surface but the mechanism is unclear.
Recently it is the leading cause of meningitis in young adult and children by about 59% of cases.
-Risk factors for meningococcal meningitis include:


Deficiencies in terminal complement components (e.g., membrane attack complex), which increases attack
rates but is associated with lower mortality rates.
Antecedent viral infection, chronic medical illness, corticosteroid use, and active or passive smoking.
7. Listeria monocytogenes meningitis: it is widespread in nature and a common food contaminant, most human
cases was food borne, associated with consumption of milk, cheese and coleslaw.
8. Gram-negative bacilli: Aerobic gram-negative include Escherichia coli (is common agent in neonates’
meningitis), Klebsiella pneumoniae, Serratia marcescens, P.aeruginosa, Salmonella species.
9. Staphylococcal meningitis: it colonized in the normal skin flora. S epidermidis is the most common cause of
meningitis in patients with CNS shunt (ventriculoperitoneal).
Additional causes of meningitis: Congenital malformation of the stapedial footplate, Head and neck surgery,
penetrating head injury, comminuted skull fracture, and osteomyelitic erosion, Skull fractures. [6]
*Epidemiology of bacterial meningitis
Bacterial meningitis is a significant source of morbidity and mortality.
Meningococcal meningitis is endemic in parts of Africa, India, and other developing areas. Periodic epidemics
occur in the so-called sub-Saharan “meningitis belt,” as well as among religious pilgrims traveling to Saudi
Arabia for the Hajj.
The incidence of neonatal bacterial meningitis is 0.25-1 case per 1000 live births. Approximately 30% of
newborns with clinical sepsis have associated bacterial meningitis.
Previously, Hib, N meningitidis, and S pneumoniae accounted for more than 80% of cases of bacterial
meningitis. Since the late 20th century, however, the epidemiology of bacterial meningitis has been
substantially changed by multiple developments.
The overall incidence of bacterial meningitis has decreased this was partially because of the widespread use
of the Hib vaccination, which decreased the incidence of H influenzae meningitis by more than 90%.
More recent prevention measures such as the pneumococcal conjugate vaccine and universal screening of
pregnant women for GBS have further changed the epidemiology of bacterial meningitis. [7]
The frequency of bacterial meningitis in children has declined due to the use of Hib vaccine, the condition is
becoming more of a disease of adults. [8]
Newborns are at highest risk for acute bacterial meningitis. After the first month of life, the peak incidence is in
infants aged 3-8 months. In addition, the incidence is increased in persons aged 60 years and older,
independent of other factors.
-Epidemiology of specific bacterial pathogens of acute meningitis:
H influenzae meningitis primarily affects infants younger than 2 years. S agalactiaemeningitis occurs principally
during the first 12 weeks of life but has also been reported in adults, primarily affecting individuals older than
age 60 years. The overall case-fatality rate in adults is 34%. Among the bacterial agents that cause
meningitis, S pneumoniae is associated with one of the highest mortalities (19-26%). [9]
*Signs and symptoms
The symptoms of bacterial meningitis can appear quickly or over several days. Typically they develop within 3
to 7 days after exposure.
-Possible signs and symptoms appearing in anyone older than 2 years :
Sudden high fever, Stiff neck, Severe headache ,Headache with nausea or vomiting
Confusion or difficulty concentrating ,Seizures and coma are the latest symptoms in meningitis and are very
serious.
A less dramatic signs and symptoms can be found such as: Sleepiness or difficulty waking,
Photophobia (increased Sensitivity to light).
But newborns and infants may show these signs:
High fever, Constant crying, Excessive sleepiness or irritability, Inactivity or sluggishness, Poor
feeding, A bulge in the soft spot on top of a baby's head (fontanel), stiffness in a baby's body and neck.
[10,11]
*Prognosis
In general Patients, who were presented with an impaired level of consciousness or seizures, have increase
risk of death and neurologic sequelae.
-In bacterial meningitis, a score was set to predict outcome including several variables:






Older age.
Increased heart rate.
Lower Glasgow Coma Scale score.
Cranial nerve palsies.
CSF leukocyte count lower than 1000/μL.
Gram-positive cocci on CSF Gram stain.
In bacterial meningitis, seizures are the most important complication it occurs in one fifth of patients and it’s
higher in patients younger than one year reaching 40% these may die as a result of CNS ischemic changes.
Even with management significant neurologic complications are noticed .Mortality increase significantly in first
year and at older age. Bacterial meningitis is fatal in 1 in 10 cases and 1 of every 7 survivors left with
impediment like defenses.
Advanced bacterial meningitis may cause brain damage and death. 50% of patients may have a serious
complications within a week, however in 30% of survivors long term sequlae are seen. Complications include
hearing loss, cortical blindness, other cranial nerve dysfunction, paralysis, muscular hypertonia, ataxia,
multiple seizures, mental motor retardation, focal paralysis, subdural effusions, hydrocephalus and cerebral
atrophy.
Risk factors for hearing loss after pneumococcal meningitis include: female gender, older age, severe
meningitis, and infection with certain pneumococcal serotypes.
Among pathogens, S pneumoniae cause the highest mortality rate with 20-30% in adults and 10% in children.
Morbidity rate is about 15 % at the time of presentation if the patient has a neurologic failure the mortality will
increase to 50% .After S pneumoniae, L monocytogenes is the one with the second highest mortality rate (1529%), then N meningitidis with (3-13%) and finally H influenzae with (3-6%). [12,13,14]
*Diagnosis
We Diagnose meningitis based on a medical history, a physical exam and certain diagnostic tests.
When a meningitis diagnosis is suspected, there are several tests that could be run to confirm a diagnosis.
NOTE: first we strongly recommend cerebrospinal fluid examination (lumbar puncture), unless
contraindications for lumbar puncture are present.
Before talking about the diagnosis techniques we would like to mention some of the clinical characteristics that
are important for the diagnosis of meningitis so in children beyond the neonatal age the most common clinical
characteristics of bacterial meningitis are fever, headache, neck stiffness and vomiting. There is no clinical sign
of bacterial meningitis present in all patients. Neonates with bacterial meningitis often present with nonspecific
symptoms. However, in adults with bacterial meningitis the most common clinical characteristics of bacterial
meningitis are fever, headache, neck stiffness and altered mental status. These Characteristic clinical signs
and symptoms can be absent and therefore bacterial meningitis should not be ruled out solely on the absence
of classic symptoms.
-Diagnosis tests used:
1.Blood cultures: Blood samples are placed in a special dish to see if it grows microorganisms, particularly
bacteria.
limitation: The yield of blood cultures decreases if the patient is pretreated with antibiotics.
2. Imaging: cranial imaging (usually computed tomography, CT) where scans of the head may show swelling
or inflammation. Such as brain abscess, subdural empyema or large cerebral infarction. we make imaging
before the lumbar puncture, if there is any Clinical characteristics identify patients with an increased risk for
space-occupying lesions which make lumbar puncture hazardous.
disadvantages : cranial imaging may lead to a substantial delay in initiation of antibiotic treatment, which is
associated with poor outcome.
3. Spinal tap (lumbar puncture): Is the procedure of taking fluid from the spine (CSF) in the lower back through
a hollow needle. This fluid is sent to the lab and analyzed to determine if there is an infection. “We determine
white blood cells (leukocyte) count, protein and glucose concentration, and perform CSF culture and Gram
stain,” this test has a good sensitivity and specificity for differentiating bacterial from aseptic meningitis and can
give us an idea if the meningitis is bacterial, viral, or fungal.” In people with meningitis, the CSF often shows a
low sugar (glucose) level along with an increased white blood cell count and increased protein. If your doctor
suspects viral meningitis or In patients with a negative CSF culture and CSF Gram stain, a DNA-based test
known as a polymerase chain reaction (PCR) and immune-chromatographic antigen testing has additive value
in the identification of the pathogen.
Limitation: Pretreatment with antibiotics decreases the yield of CSF culture by 10–20%. [15]
*Biomarkers
New Biomarker for Bacterial Meningitis:
Several studies have investigated the diagnostic accuracy of procalcitonin (PCT) levels in blood or
cerebrospinal fluid (CSF) in bacterial meningitis (BM), but the results were heterogeneous.
The aim of the study was to ascertain the diagnostic accuracy of PCT as a marker for BM detection.
Acute meningitis (AM) is an extremely severe and life-threatening infection, and early diagnosis and prompt
treatment are critically important for AM patients due to the high rates of mortality and morbidity associated
with the infection. AM is classified into bacterial meningitis (BM) and nonbacterial meningitis (NBM). [16]
The differentiating between acute bacterial and non bacterial meningitis is challenging because they share
many similar clinical symptoms, such as fever and headache. [17]
Positive cerebrospinal fluid (CSF) bacterial culture, Gram staining, or detection of bacterial antigens in the CSF
represent the gold standard of clinical testing in BM diagnosis. However, although they have high specificity,
the sensitivity is poor. Furthermore, bacterial culture is time-consuming. [18]
Procalcitonin (PCT) is a 116-amino-acid protein that is produced primarily by the C cells of the thyroid gland
and secreted from leukocytes in the peripheral blood. [19]
In healthy individuals, PCT is secreted at levels that are below the detectable limit. However, serum PCT levels
increase markedly in patients suffering from bacterial infections. [20]
Twenty-two studies were included in this systematic review and meta-analysisThe references used for BM
diagnosis varied among the included studies. [21]
All studies set CSF culture as an item of reference, and a few studies set one or more of the following as
additional items of reference: CSF Gram staining, blood culture, CSF antigen test, clinical signs or symptoms,
and laboratory findings. Thirteen of the studies used the immunoluminometric assay (ILMA) LUMI test
(BRAHMS Diagnostica, Berlin, Germany) to determine PCT.
The results of this meta-analysis indicate that CSF PCT and blood PCT were both effective biomarkers for BM
diagnosis. The diagnostic accuracy of elevated blood PCT appeared to be superior to CSF PCT. We also
found that blood PCT was associated with a higher pooled sensitivity and specificity when compared with CSF
PCT. This finding suggests that blood PCT has superior diagnostic potential when compared with CSF PCT.
*Management
The delay in treatment has been associated with a poorer outcome. Thus, first we should start treatment with
wide-spectrum antibiotics while confirmatory tests are being conducted. After identification of the pathogen
and determination of susceptibilities, targeted antibiotic therapy as appropriate for patient age and condition
and we may use Steroid (typically, dexamethasone) therapy.
-We should take care for the following in the Initial measures:
1. Shock or hypotension here intravenous fluids should be administered , in children routine intravenous fluids
for two days may improve outcomes in those who arrive at hospital after being sick for some time.
2. Altered mental status – Seizures are treated with anticonvulsants , airway protection (Mechanical ventilation)
if the level of consciousness is very low, or if there is evidence of respiratory failure.
3. Stable with normal vital signs: assess oxygen and IV access.
Rapid transport to the emergency department (ED) should always be considered given that meningitis can
cause a number of early severe complications, so we should be able to identify these complications early and
to admit the person to an intensive care unit if deemed necessary.
[22,23]
*Treatment
Bacterial meningitis (including meningococcal meningitis, Haemophilus influenza meningitis,
and staphylococcal meningitis) is a neurologic emergency that is associated with significant morbidity and
mortality. Initiation of empiric antibacterial therapy is therefore essential for better outcome. [24]
Appropriate antibiotic treatment for the most common types of bacterial meningitis reduces the risk of death.
Mortality is higher with pneumococcal meningitis.
The chosen antibiotic should attain adequate levels in the CSF, and its ability to do so usually depends on its
lipid solubility, molecular size, and protein-binding capacity, as well as on the patient’s degree of meningeal
inflammation. The penicillins, certain cephalosporins (i.e., third- and fourth-generation agents), the
carbapenems, fluoroquinolones, and rifampin provide high CSF levels. [25]
-Treatment is dependent on the age of the patient and predisposing features as following:
1. Age 0-4 week >> Ampicillin plus either cefotaxime or an aminoglycoside.
2. Age 1 month – 50 years >> Vancomycin plus cefotaxime or ceftriaxone.
3. Age >50 years >> Vancomycin plus ampicillin plus ceftriaxone or cefotaxime plus vancomycin.
4. Impaired cellular immunity>> Vancomycin plus ampicillin plus either cefepime or meropenem.
5. Recurrent meningitis >> Vancomycin plus cefotaxime or ceftriaxone.
6. Basilar skull fracture >> Vancomycin plus cefotaxime or ceftriaxone.
7. Head trauma, neurosurgery, or CSF shunt >> Vancomycin plus ceftazidime, cefepime, or meropenem.
Note: Add ampicillin if Listeria monocytogenes is a suspected pathogen. [26]
-Intrathecal antibiotics:
Intrathecal administration of antibiotics can be considered in patients with nosocomial meningitis that does not
respond to IV antibiotics. Although the FDA has not approved any antibiotics for intraventricular use,
vancomycin and gentamicin are often used in this setting. Other agents used intrathecally include amikacin,
polymyxin B, and colistin. [27]
*Vaccination

Pneumococcal Vaccination.

Hib Vaccination (Haemophilus influenzae type b (Hib)).
-Three types of meningococcal vaccines are used:
1. Meningococcal conjugate vaccine (MCV4) - These include Menactra and Menveo.
2. Meningococcal polysaccharide vaccine (MPSV4) - Menoimune.
3. Serogroup B Meningococcal B - There are two MenB vaccines. Trumenba (MenB-FHbp) and Bexsero (MenB4C).
MCV4 and MPSV4 can prevent 70% of the types of meningococcal disease. Both are effective in nine out of 10
people. MCV4 tends to give longer protection and is better at preventing transmission of the disease.
A new study in Africa presented that Group A Neisseria meningitidis has been a major cause of bacterial
meningitis. It is an encapsulated pathogen, and antibodies against the capsular polysaccharide are protective.
Polysaccharide–protein conjugate vaccines have proven to be highly effective against several different
encapsulated bacterial pathogens. Purified polysaccharide vaccines have been used to control group A
meningococcal (MenA) epidemics with minimal success.
A monovalent MenA polysaccharide–tetanus toxoid conjugate was therefore developed. This vaccine was
developed by scientists working with the Meningitis Vaccine Project.
A high-efficiency conjugation method was developed in the Laboratory for purification of the group A
polysaccharide and used its tetanus toxoid as the carrier protein to produce the now-licensed, highly effective
MenAfriVac conjugate immunotherapy.
-Two licensed formulations available:
1. MenAfriVac 10 µg of purified Men A polysaccharide antigen conjugated with tetanus toxoid (PsA-TT) per
dose • for use in those aged 1–29 years.
2. MenAfriVac 5 µg for use in infants and children aged 3–24 months. [28]
*Patient education
Patients and parents of young children should be educated about the benefits of vaccination in preventing
meningitis. Vaccination against N meningitidis is recommended for all people.
Close contact with patients of known or suspected N meningitidis or Hib meningitis may require education
regarding the need for prophylaxis. All contacts should be instructed to come to the emergency department
immediately at the first sign of fever, sore throat, rash, or symptoms of meningitis. Rifampin prophylaxis only
eradicates the organism from the nasopharynx; it is ineffective against invasive disease.
-These steps can help prevent meningitis:
1. Wash your hands. Careful hand-washing helps prevent germs. Teach children to wash their hands often,
especially before eating and after using the toilet, spending time in a crowded public place or petting animals.
Show them how to vigorously and thoroughly wash and rinse their hands.
2. Practice good hygiene. Don't share drinks, foods, and straws, eating utensils, lip balms or toothbrushes with
anyone else. Teach children and teens to avoid sharing these items too.
3. Stay healthy. Maintain your immune system by getting enough rest, exercising regularly, and eating a
healthy diet with plenty of fresh fruits, vegetables and whole grains.
4. Cover your mouth. When you need to cough or sneeze, be sure to cover your mouth and nose.
If you're pregnant, take care with food. Reduce your risk of listeriosis by cooking meat, including hot dogs and
deli meat, to 165 F (74 C). Avoid cheeses made from unpasteurized milk. Choose cheeses that are clearly
labeled as being made with pasteurized milk.
References:
1. Mann K, Jackson MA. Meningitis. Pediatr Rev. 2008 Dec. 29(12):417-29; quiz 430 , Characterization of the Neisseria
meningitidis Helicase RecG Getachew Tesfaye Beyene1¤ , Seetha V. Balasingham2 , Stephan A. Frye2 , Amine Namouchi2
, Håvard Homberset1 , Shewit Kalayou1 , Tahira Riaz1 , Tone Tønjum1,2* 1 Department of Microbiology, University of Oslo,
Oslo, Norway, 2 Department of Microbiology, Oslo University Hospital (Rikshospitalet), Oslo, Norway October 13, 2016.
2. Mann K, Jackson MA. Meningitis. Pediatr Rev. 2008 Dec. 29(12):417-29; quiz 430.
3. Ginsberg L, Kidd D. Chronic and recurrent meningitis. Pract Neurol. 2008 Dec. 8(6):348-61.
4. Berkhout B. Infectious diseases of the nervous system: pathogenesis and worldwide impact. IDrugs. 2008 Nov.
11(11):791-5.
5. Koedel U, Klein M, Pfister HW. New understandings on the pathophysiology of bacterial meningitis. Curr Opin Infect Dis.
2010 Jun. 23(3):217-23.
6. Thigpen MC, Whitney CG, Messonnier NE, Zell ER, Lynfield R, Hadler JL, et al. Bacterial meningitis in the United States,
1998-2007. N Engl J Med. 2011 May 26. 364(21):2016-25.
7. Thigpen MC, Whitney CG, Messonnier NE, Zell ER, Lynfield R, Hadler JL, et al. Bacterial meningitis in the United States,
1998-2007. N Engl J Med. 2011 May 26. 364(21):2016-25.
8. Thigpen, M, Rosenstein, NE, Whitney, CG. Bacterial meningitis in the United States--1998-2003. Presented at the 43rd
Annual Meeting of the Infectious Diseases Society of America, San Francisco, CA. October 2005;65.
9. Thigpen MC, Whitney CG, Messonnier NE, Zell ER, Lynfield R, Hadler JL, et al. Bacterial meningitis in the United States,
1998-2007. N Engl J Med. 2011 May 26. 364(21):2016-25.
10. Mann K, Jackson MA. Meningitis. Pediatr Rev. 2008 Dec. 29(12):417-29; quiz 430.
11. Ginsberg L, Kidd D. Chronic and recurrent meningitis. Pract Neurol. 2008 Dec. 8(6):348-61.
12. Berkhout B. Infectious diseases of the nervous system: pathogenesis and worldwide impact. IDrugs. 2008 Nov.
11(11):791-5.
13. Schut ES, Brouwer MC, Scarborough M, Mai NT, Thwaites GE, Farrar JJ, et al. Validation of a Dutch risk score predicting
poor outcome in adults with bacterial meningitis in Vietnam and Malawi. PLoS One. 2012. 7(3):e34311.
14. Worsøe L, Cayé-Thomasen P, Brandt CT, Thomsen J, Østergaard C. Factors associated with the occurrence of hearing
loss after pneumococcal meningitis. Clin Infect Dis. 2010 Oct 15. 51(8):917-24.
15. ESCMID guideline: diagnosis and treatment of acute bacterial meningitis D. van de Beek1 , C. Cabellos2 , O. Dzupova3 ,
S. Esposito4 , M. Klein5 , A. T. Kloek1 , S. L. Leib6 , B. Mourvillier7 , C. Ostergaard8 , P. Pagliano9 , H. W. Pfister5 , R. C.
Read10, O. Resat Sipahi11 and M. C. Brouwer1 , for the ESCMID Study Group for Infections of the Brain (ESGIB)
Original Submission: 10 December 2015; Accepted: 11 January 2016 Editor: D. Raoult Article published online: 7 April 2016.
16. Spanos A, Harrell FE, Jr, Durack DT. Differential diagnosis of acute meningitis. An analysis of the predictive value of
initial observations. JAMA 1989; 262:2700–2707.
17. (van de Beek D, de Gans J, Spanjaard L, et al. Clinical features and prognostic factors in adults with bacterial
meningitis. N Engl J Med 2004; 351:1849–1859.
18. Mekitarian Filho E, Horita SM, Gilio AE, et al. Cerebrospinal fluid lactate level as a diagnostic biomarker for
bacterial meningitis in children. Int J Emerg Med 2014; 7:14. / White K, Ostrowski K, Maloney S, et al. The utility of
cerebrospinal fluid parameters in the early microbiological assessment of meningitis. Diagn Microbiol Infect
Dis 2012; 73:27–30.
19. Meisner M. Update on procalcitonin measurements. Ann Lab Med 2014; 34:263–273.
20. Meisner M. Update on procalcitonin measurements. Ann Lab Med 2014; 34:263–273 / Wacker C, Prkno A,
Brunkhorst FM, et al. Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis. Lancet
Infect Dis 2013; 13:426–435.
21. Gendrel D, Raymond J, Assicot M, et al. Measurement of procalcitonin levels in children with bacterial or viral
meningitis. Clin Infect Dis 1997; 24:1240–1242. / Shen HY, Gao W, Cheng JJ, et al. Direct comparison of the
diagnostic accuracy between blood and cerebrospinal fluid procalcitonin levels in patients with meningitis. Clin
Biochem 2015; 48:1079–1082.
22. Author Rodrigo Hasbun, MD, MPH Associate Professor of Medicine, Section of Infectious Diseases, University of Texas
Medical School at Houston Disclosure: Received honoraria from Medicine''''''''s Company for speaking and teaching;
Received honoraria from Cubicin for speaking and teaching; Received honoraria from Theravance for speaking and teaching;
Received honoraria from Pfizer for speaking and teaching. Updated: Feb 16, 2016.Nationwide implementation of adjunctive
dexamethasone therapy for pneumococcal meningitis.
23. Heyderman RS, Lambert HP, O'Sullivan I, Stuart JM, Taylor BL, Wall RA (February 2003). "Early management of
suspected bacterial meningitis and meningococcal septicaemia in adults" (PDF). The Journal of infection. 46 (2): 75–
7.doi:10.1053/jinf.2002.1110. PMID 12634067. – formal guideline at British Infection Society; UK Meningitis Research Trust
(December 2004). "Early management of suspected meningitis and meningococcal septicaemia in immunocompetent adults".
British Infection Society Guidelines. Retrieved 19 October 2008.
24. Gilbert DN, Moellering RC Jr, Sande MA. Antimicrobial Therapy. In: Sanford Guide to Antimicrobial Therapy. 33rd ed.
March 15, 2003, van de Beek D, Brouwer MC, Thwaites GE, Tunkel AR. Advances in treatment of bacterial
meningitis.Lancet. 2012 Nov 10. 380(9854):1693-702.
25. Brouwer MC, Heckenberg SG, de Gans J, Spanjaard L, Reitsma JB, van de Beek D. Nationwide implementation of
adjunctive dexamethasone therapy for pneumococcal meningitis. Neurology. 2010 Oct 26. 75(17):1533-9.
26. van de Beek D, Brouwer MC, Thwaites GE, Tunkel AR. Advances in treatment of bacterial meningitis.Lancet. 2012 Nov
10. 380(9854):1693-702.
27. (van de Beek D, Drake JM, Tunkel AR. Nosocomial bacterial meningitis. N Engl J Med. 2010 Jan 14. 362(2):146-54.).
28. (Daugla DM, Gami JP, Gamougam K, et al. Effect of a serogroup A meningococcal conjugate vaccine (PsA-TT) on
serogroup A meningococcal meningitis and carriage in Chad: a community study. Lancet. 2014; 383: 40-47.).